The advantages of controlled release products are well known and documented in the pharmaceutical art. Advantages include the ability to maintain a desirable blood level of a medicament over an extended period, such as twenty four hours, by minimizing the peak to trough variations in plasma concentrations. Also, patient compliance is increased by reducing the number of administrations necessary to achieve a desired therapeutic effect. Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. While many controlled and sustained release formulations are already known, certain moderately to poorly soluble drugs present formulation difficulties which render them unsuitable for sustained release carriers which might be acceptable for other drugs, such as those that are relatively soluble. It is often impossible to predict whether a particular sustained release formulation will provide the desired release profile for a relatively insoluble drug, and it has generally been found that it is necessary to carry out considerable experimentation to obtain sustained release formulations having the desired bioavailability when ingested, particularly for drugs that are poorly soluble in water.
An example of relatively insoluble drugs which are difficult to formulate into controlled release formulations is the sulfonylurea class of antidiabetic drugs. Sulfonylureas are effective to control blood sugar levels in diabetics, in particular, type II diabetic patients who are unable to achieve control through dietary restriction alone. Sulfonylureas are believed to stimulate the release of insulin from the pancreatic islet cells via receptors that are reported to be ATP sensitive potassium channels.
In humans, acute stimulation of insulin secretion by sulfonylureas in response to a meal is believed to be of major importance, thus the sulfonylureas require endogenous insulin secretion in order to achieve beneficial results. Fasting insulin levels are not elevated even on long-term administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of Glipizide (a sulfonylurea) in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. It is also believed that extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. For example, although the mechanism by which sulfonylureas lower blood glucose during long-term administration has not been clearly established, it has been reported that these drugs enhance the sensitivity of tissue insulin receptors after prolonged treatment. The subject is generally reviewed in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, the disclosure of which is incorporated by reference herein in its entirety.
The sulfonylureas are considered to be subdivided into two subcategories: the first generation agents, e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, and the second generation agents, e.g., glyburide (glibenclamide), glipizide and gliclazide.
Tolbutamide is practically insoluble in water but forms water-soluble salts with alkali. Tolbutamide is commercially available in 250 mg or 500 mg immediate release tablets. The immediate release formulation is typically administered twice to three times a day.
Tolazamide is also relatively insoluble in water. The solubility at pH 6.0 (mean urinary pH) is 27.8 mg per 100 ml. Tolazamide is commercially available in 100 and 250 mg immediate release tablets. The immediate release formulation is typically administered twice a day. Acetohexamide practically insoluble in water and ether, soluble in pyridine and dilute solutions of alkali hydroxides, and slightly soluble in alcohol and chloroform. Acetohexamide is commercially available in 250 and 500 mg, immediate release tablets. The immediate release formulation is typically administered twice a day.
Chlorpropamide is soluble in water at pH 6.0 (2.2 mg/ml) and practically non-soluble in water at pH 7.3.
Glyburide is sparingly soluble in water and soluble in organic solvents. Glyburide is available as tablets of 1.25 mg, 2.5 mg. and 5 mg strengths for oral administration and is typically administered twice a day.
Glipizide is insoluble in water and alcohol but soluble in alkali, e.g., 0.1N sodium hydroxide. The immediate release formulation is typically administered twice a day.
The first generation agents vary widely in their pharmacokinetics, with acetohexamide, tolbutamide and tolazamide having a half-life of about 4 to 7 hours, necessitating repeated doses throughout the day, whereas chlorpropamide has a half life of from 24 to 48 hours. The second generation agents are about a hundred times more potent, by weight, than are the first generation agents, but generally have a shorter half-life, ranging from about 1.5 to 5 hours.
Glipizide, is representative of the second generation sulfonylureas. Gastrointestinal absorption of glipizide is uniform, rapid and essentially complete, providing peak plasma levels concentrations about 1 to 3 hours after a single oral dose. Normal subjects demonstrate an elimination half-life ranging from about 2 to about 4 hours after both intravenous and oral administration. In addition, glipizide does not accumulate in the plasma following repeated oral dosing. Glipizide tablets are available, e.g., in 5 and 10 mg immediate release formulations (e.g., as Glucotrol.RTM., marketed by Pratt Pharmaceuticals).
Immediate release tablets formulated with a sulfonylurea based on an acidified and/or alkalized excipient and an inert polar solvent, such as polyethylene glycol, are described by U.S. Pat. No. 4,696,815. These pH regulated, immediate release formulations are described as improving the dissolution of acidic, amphoteric or basic antidiabetic sulfonylurea compounds, respectively. For example, the alkalized excipient is said to promote improved dissolution of glipizide, which is an acid compound. An analogous immediate release formulation with an acidified and/or alkalized excipient, an inert polar solvent and polyvinylpyrrolidone is also described by U.S. Pat. No. 4,696,815.
Erodible poly(orthoester) or poly(orthocarbonate) devices for implantation or insertion into a patient are described by U.S. Pat. No. 4,346,709, for delivering a drug in a controlled manner, including oral hypoglycemic drugs such as the sulfonylurea hypoglycemics, acetohexamide, glypinamide, chlorpropamide, tolazamide, tolbutamide, phenformin.
A controlled release delivery system using melt spun biodegradable polymers as a carrier or host material for a bio-effecting agent such as a pharmaceutical active or a hormonal compound, including glipizide, for e.g., oral administration, is described by U.S. Pat. No. 5,518,730.
Controlled release microspheres for administration by, e.g., the oral route and comprising polylactic acid and a water soluble physiologically active substance and having a mean particle size of from about 0.01 mu m to 300 mu m are described by U.S. Pat. No. 5,100,669 as including active substances such as the antidiabetic agents glipizide, glymidine sodium, phenformin hydrochloride, methformin, buformin hydrochloride.
Uniformity and predictability of therapeutic levels of sulfonylureas and resulting blood sugar levels are considered to be desirable in the management of diabetes patents, and in particular, for the management of type II diabetic patients. For example, in tests with art-known extended release glipizide (formulations based on orally ingestible osmotic devices, as discussed hereinbelow) it has been shown that fasting plasma glucose levels were significantly lower in patients treated with controlled release glipizide than with immediate-release glipizide (Berelowitz et al., 1994, Diabetes Care 17(12):1460-4).
Extended release sulfonylurea formulations with improved dissolution properties, and particularly, extended release formulations of second generation sulfonylureas, are therefore a desirable addition to the medical treatment of diabetes, including type II diabetes. Of these second generation drugs, efforts to provide controlled release have focused on glipizide. Art-known extended release glipizide formulations are available as osmotic based dosage forms, such as, for example, Glucotrol XL Extended Release Tablet.RTM. (Pratt Pharmaceuticals; 5 to 60 mg unit doses). As with other art-known extended release glipizide, discussed hereinbelow, Glucotrol XL.RTM. is prepared as an osmotic pump formulation. Specifically, Glucotrol XL.RTM. is prepared as an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the osmotically active material, the tablet pressure increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small laser-drilled orifice in the membrane on the drug side of the tablet.
Other osmotic pump devices and formulations for administering glipizide are described in U.S. Pat. Nos. 5,091,190 and 5,024,843 (Kucrynski et. al.) and in U.S. Pat. No. 4,803,076 (Gautman). These patents describe the delivery of glipizide in a controlled manner by the use of an oral formulation based on another osmotic pump design. U.S. Pat. No. 4,792,448 (Gautman) has also described the zero order release of glipizide using a device described as a strip covered by an impermeable wall with uncovered areas. All of these formulations therefore are prepared from a plurality of osmotic pump devices that require complex manufacturing processes with attendant high costs.
Therefore, there has not previously been a fully satisfactory and economical formulation for providing a predictable and uniform treatment regimen, which avoids the need for the construction of complex devices for oral administration and that have the further advantage of simplifying treatment and improving patient compliance while both enhancing the bioavailability of the antidiabetic drug and prolonging the release of the drug.
A significant problem facing the pharmaceutical formulator attempting to prepare a bioavailable oral sustained release dosage form of a sulfonylurea relates to the ability of the dosage form to release the drug over the desired period of time to such an extent that the sulfonylurea content of the dosage form will be effectively bioavailable. One aspect of this problem is the fact that sulfonylureas are relatively insoluble and therefore inherently difficult to be solubilized from an oral dosage form in the gastrointestinal tract and then be absorbed through the walls of the gastrointestinal tract. This solubility and bioavailability problem has been overcome with respect to immediate release oral sulfonylurea dosage form by utilizing a solubilizing agent, as discussed above. However, such agents are expected to cause the fast, i.e., immediate, release of all of the sulfonylurea when orally administered. Therefore, the use of such solubilizing agents would not necessarily be considered desirable in sustained release oral dosage forms, where the goal is to slow the release of drug from the dosage form over an extended period of time.
Thus, there is a continuing need in the art for a relatively simple and economical controlled release sulfonylurea formulation for oral administration that is fully bioavailable and suitable for administration once every 24 hours.